Erythromyacin antibiotic product, use and formulation thereof

ABSTRACT

An antibiotic product, in particular an erythromyacin, is comprised of at least three dosages forms, each of which has a different release profile, with the C max  for the antibiotic product being reached in less than about twelve hours. In one embodiment, there is an immediate release dosage form, as well as two or more delayed release dosage forms, with each of the dosage forms having a different release profile, wherein each reaches a C max  at different times.

This application is a continuation-in-part of U.S. application Ser. No.09/792,092, filed on Feb. 22, 2001, which is a continuation-in-part ofU.S. application Ser. No. 09/687,229, filed on Oct. 13, 2000, and alsoclaims the priority of U.S. Provisional Application Serial No.60/184,546 filed on Feb. 24, 2000.

This invention relates to an antibiotic product, as well as the use andformulation thereof. The invention further relates to an erythromyacinantibiotic product, in particular an erythromyacin derivative or amacrolide or a ketolite (including derivatives thereof such as salts,esters, etc.); in particular Clarithromycin.

A wide variety of antibiotics have been used, and will be used, in orderto combat bacterial infection. In general, such antibiotics can beadministered by a repeated dosing of immediate release dosage forms,which results in poor compliance or as a controlled release formulation(slow release) at higher administered doses. The present invention isdirected to providing for an improved antibiotic product.

In accordance with one aspect of the present invention, there isprovided an antibiotic pharmaceutical product which is comprised of atleast two, preferably at least three, antibiotic dosage forms. Suchdosage forms are formulated so that each of the dosage forms has adifferent release profile.

In a particularly preferred embodiment, there are at least two,preferably at least three dosage forms, each of which has a differentrelease profile and the release profile of each of the dosage forms issuch that the dosage forms each start release of the antibioticcontained therein at different times after administration of theantibiotic product.

Thus, in accordance with an aspect of the present invention, there isprovided a single or unitary antibiotic product that has containedtherein at least two, preferably at least three antibiotic dosage forms,each of which has a different release profile, whereby the antibioticcontained in each of such dosage forms is released at different times.

In accordance with a further aspect of the invention, the antibioticproduct may be comprised of at least four different dosage forms, eachof which starts to release the antibiotic contained therein at differenttimes after administration of the antibiotic product.

The antibiotic product generally does not include more than five dosageforms with different release times.

In accordance with a preferred embodiment, the antibiotic product has anoverall release profile such that when administered the maximum serumconcentration of the total antibiotic released from the product isreached in less than twelve hours, preferably in less than eleven hours.In an embodiment, the maximum serum concentration of the totalantibiotic released from the antibiotic product is achieved no earlierthan four hours after administration.

In accordance with one preferred embodiment of the invention, there areat least three dosage forms. One of the at least three dosage forms isan immediate release dosage form whereby initiation of release of theantibiotic therefrom is not substantially delayed after administrationof the antibiotic product. The second and third of the at least threedosage forms is a delayed dosage form (which may be a pH sensitive or anon-pH sensitive delayed dosage form, depending on the type ofantibiotic product), whereby the antibiotic released therefrom isdelayed until after initiation of release of the antibiotic from theimmediate release dosage form. More particularly, the antibiotic releasefrom the second of the at least two dosage forms achieves a C_(max)(maximum serum concentration in the serum) at a time after theantibiotic released from the first of the at least three dosage formsachieves a C_(max) in the serum, and the antibiotic released from thethird dosage form achieves a C_(max) in the serum after the C_(max) ofantibiotic released from the second dosage form.

In one embodiment, the second of the at least two dosage forms initiatesrelease of the antibiotic contained therein at least one hour after thefirst dosage form, with the initiation of the release therefromgenerally occurring no more than six hours after initiation of releaseof antibiotic from the first dosage form of the at least three dosageforms.

In general, the immediate release dosage form produces a C_(max) for theantibiotic released therefrom within from about 0.5 to about 2 hours,with the second dosage form of the at least three dosage forms producinga C_(max) for the antibiotic released therefrom in no more than aboutfour hours. In general, the C_(max) for such second dosage form isachieved no earlier than two hours after administration of theantibiotic product; however, it is possible within the scope of theinvention to achieve C_(max) in a shorter period of time.

As hereinabove indicated, the antibiotic product may contain at leastthree or at least four or more different dosage forms. For example, ifthe antibiotic product includes a third dosage form, the antibioticreleased therefrom reaches a C_(max) at a time later than the C_(max) isachieved for the antibiotic released from each of the first and seconddosage forms. In a preferred embodiment, release of antibiotic from thethird dosage form is started after initiation of release of antibioticfrom both the first dosage form and the second dosage form. In oneembodiment, C_(max) for antibiotic release from the third dosage form isachieved within eight hours.

In another embodiment, the antibiotic product contains at least fourdosage forms, with each of the at least four dosage forms havingdifferent release profiles, whereby the antibiotic release from each ofthe at least four different dosage forms achieves a C_(max) at adifferent time.

As hereinabove indicated, in a preferred embodiment, irrespective ofwhether the antibiotic contains at least two or at least three or atleast four different dosage forms each with a different release profile,C_(max) for all the antibiotic released from the antibiotic product isachieved in less than twelve hours, and more generally is achieved inless than eleven hours.

In a preferred embodiment, the antibiotic product is a once a dayproduct, whereby after administration of the antibiotic product, nofurther product is administered during the day; i.e., the preferredregimen is that the product is administered only once over a twenty-fourhour period. Thus, in accordance with the present invention, there is asingle administration of an antibiotic product with the antibiotic beingreleased in a manner such that overall antibiotic release is effectedwith different release profiles in a manner such that the overallC_(max) for the antibiotic product is reached in less than twelve hours.The term single administration means that the total antibioticadministered over a twenty-four hour period is administered at the sametime, which can be a single tablet or capsule or two or more thereof,provided that they are administered at essentially the same time.

Applicant has found that a single dosage antibiotic product comprised ofat least three antibiotic dosage forms each having a different releaseprofile is an improvement over a single dosage antibiotic productcomprised of an antibiotic dosage form having a single release profile.Each of the dosage forms of antibiotic in a pharmaceutically acceptablecarrier may have one or more antibiotics and each of the dosage formsmay have the same antibiotic or different antibiotics.

It is to be understood that when it is disclosed herein that a dosageform initiates release after another dosage form, such terminology meansthat the dosage form is designed and is intended to produce such laterinitiated release. It is known in the art, however, notwithstanding suchdesign and intent, some “leakage” of antibiotic may occur. Such“leakage” is not “release” as used herein.

If at least four dosage forms are used, the fourth of the at least fourdosage form may be a sustained release dosage form or a delayed releasedosage form. If the fourth dosage form is a sustained release dosageform, even though C_(max) of the fourth dosage form of the at least fourdosage forms is reached after the C_(max) of each of the other dosageforms is reached, antibiotic release from such fourth dosage form may beinitiated prior to or after release from the second or third dosageform.

The antibiotic product of the present invention, as hereinabovedescribed, may be formulated for administration by a variety of routesof administration. For example, the antibiotic product may be formulatedin a way that is suitable for topical administration; administration inthe eye or the ear; rectal or vaginal administration; as nose drops; byinhalation; as an injectable; or for oral administration. In a preferredembodiment, the antibiotic product is formulated in a manner such thatit is suitable for oral administration.

For example, in formulating the antibiotic product for topicaladministration, such as by application to the skin, the at least twodifferent dosage forms, each of which contains an antibiotic, may beformulated for topical administration by including such dosage forms inan oil-in-water emulsion, or a water-in-oil emulsion. In such aformulation, the immediate release dosage form is in the continuousphase, and the delayed release dosage form is in a discontinuous phase.The formulation may also be produced in a manner for delivery of threedosage forms as hereinabove described. For example, there may beprovided an oil-in-water-in-oil emulsion, with oil being a continuousphase that contains the immediate release component, water dispersed inthe oil containing a first delayed release dosage form, and oildispersed in the water containing a third delayed release dosage form.

It is also within the scope of the invention to provide an antibioticproduct in the form of a patch, which includes antibiotic dosage formshaving different release profiles, as hereinabove described.

In addition, the antibiotic product may be formulated for use in the eyeor ear or nose, for example, as a liquid emulsion. For example, thedosage form may be coated with a hydrophobic polymer whereby a dosageform is in the oil phase of the emulsion, and a dosage form may becoated with hydrophilic polymer, whereby a dosage form is in the waterphase of the emulsion.

Furthermore, the antibiotic product with at least three different dosageforms with different release profiles may be formulated for rectal orvaginal administration, as known in the art. This may take the form of acream or emulsion, or other dissolvable dosage form similar to thoseused for topical administration.

As a further embodiment, the antibiotic product may be formulated foruse in inhalation therapy by coating the particles and micronizing theparticles for inhalation.

In a preferred embodiment, the antibiotic product is formulated in amanner suitable for oral administration. Thus, for example, for oraladministration, each of the dosage forms may be used as a pellet or aparticle, with a pellet or particle then being formed into a unitarypharmaceutical product, for example, in a capsule, or embedded in atablet, or suspended in a liquid for oral administration.

Alternatively, in formulating an oral delivery system, each of thedosage forms of the product may be formulated as a tablet, with each ofthe tablets being put into a capsule to produce a unitary antibioticproduct. Thus, for example, antibiotic products may include a firstdosage form in the form of a tablet that is an immediate release tablet,and may also include two or more additional tablets, each of whichprovides for a delayed release of the antibiotic, as hereinabovedescribed, whereby the C_(max) of the antibiotic released from each ofthe tablets is reached at different times, with the C_(max) of the totalantibiotic released from the antibiotic product being achieved in lessthan twelve hours.

The formulation of an antibiotic product including at least three dosageforms with different release profiles for different routes ofadministration is deemed to be within the skill of the art from theteachings herein. As known in the art, with respect to delayed release,the time of release can be controlled by the concentration ofantibiotics in the coating and/or the thickness of the coating.

In formulating an antibiotic product in accordance with the invention,in one embodiment, the immediate release dosage form of the productgenerally provides from about 20% to about 50% of the total dosage ofantibiotic to be delivered by the product, with such immediate releasedosage forms generally providing at least 25% of the total dosage of theantibiotic to be delivered by the product. In many cases, the immediaterelease dosage form provides from about 20% to about 30% of the totaldosage of antibiotic to be delivered by the product; however, in somecases it may be desirable to have the immediate release dosage formprovide for about 45% to about 50% of the total dosage of antibiotic tobe delivered by the product.

The remaining dosage forms deliver the remainder of the antibiotic. Ifmore than one delayed release dosage form is used, in one embodiment,each of the delayed release dosage forms may provide about equal amountsof antibiotic; however, they may also be formulated so as to providedifferent amounts.

In accordance with the present invention, each of the dosage formscontains the same antibiotic; however, each of the dosage forms maycontain more than one antibiotic.

In one embodiment, where the composition contains one immediate releasecomponent and two delayed release components, the immediate releasecomponent provides from 20% to 35% (preferably 20% to 30%), by weight,of the total antibiotic; where there is three delayed releasecomponents, the immediate release component provides from 15% to 30%, byweight, of the total antibiotic; and where there are four delayedrelease components, the immediate release component provides from 10% to25%, by weight, of the total antibiotic.

With respect to the delayed release components, where there are twodelayed release components, the first delayed release component (the onereleased earlier in time) provides from 30% to 60%, by weight, of thetotal antibiotic provided by the two delayed release components with thesecond delayed release component providing the remainder of theantibiotic.

Where there are three delayed release components, the earliest releasedcomponent provides 20% to 35% by weight of the total antibiotic providedby the three delayed release components, the next in time delayedrelease component provides from 20% to 40%, by weight, of the antibioticprovided by the three delayed release components and the last in timeproviding the remainder of the antibiotic provided by the three delayedrelease components.

When there are four delayed release components, the earliest delayedrelease component provides from 15% to 30%, by weight, the next in timedelayed release component provides from 15% to 30%, the next in timedelayed release component provides from 20% to 35%, by weight, and thelast in time delayed release component provides from 20% to 35%, byweight, in each case of the total antibiotic provided by the fourdelayed release components.

The Immediate Release Component

The immediate release portion of this system can be a mixture ofingredients that breaks down quickly after administration to release theantibiotic. This can take the form of either a discrete pellet orgranule that is mixed in with, or compressed with, the other threecomponents.

The materials to be added to the antibiotics for the immediate releasecomponent can be, but are not limited to, microcrystalline cellulose,corn starch, pregelatinized starch, potato starch, rice starch, sodiumcarboxymethyl starch, hydroxypropylcellulose,hydroxypropylmethylcellulose, hydroxyethylcellulose, ethylcellulose,chitosan, hydroxychitosan, hydroxymethylatedchitosan, cross-linkedchitosan, cross-linked hydroxymethyl chitosan, maltodextrin, mannitol,sorbitol, dextrose, maltose, fructose, glucose, levulose, sucrose,polyvinylpyrrolidone (PVP), acrylic acid derivatives (Carbopol,Eudragit, etc.), polyethylene glycols, such a low molecular weight PEGs(PEG2000-10000) and high molecular weight PEGs (Polyox) with molecularweights above 20,000 daltons.

It may be useful to have these materials present in the range of 1.0 to60% (W/W).

In addition, it may be useful to have other ingredients in this systemto aid in the dissolution of the drug, or the breakdown of the componentafter ingestion or administration. These ingredients can be surfactants,such as sodium lauryl sulfate, sodium monoglycerate, sorbitanmonooleate, sorbitan monooleate, polyoxyethylene sorbitan monooleate,glyceryl monostearate, glyceryl monooleate, glyceryl monobutyrate, oneof the non-ionic surfactants such as the Pluronic line of surfactants,or any other material with surface active properties, or any combinationof the above.

These materials may be present in the rate of 0.05-15% (W/W).

The Non-pH Sensitive Delayed Release Component

The components in this composition are the same immediate release unit,but with additional polymers integrated into the composition, or ascoatings over the pellet or granule.

Materials that can be used to obtain a delay in release suitable forthis component of the invention can be, but are not limited to,polyethylene glycol (PEG) with molecular weight above 4,000 daltons(Carbowax, Polyox), waxes such as white wax or bees wax, paraffin,acrylic acid derivatives (Eudragit), propylene glycol, andethylcellulose.

Typically these materials can be present in the range of 0.5-25% (W/W)of this component.

The pH Sensitive (Enteric) Release Component

The components in this composition are the same as the immediate releasecomponent, but with additional polymers integrated into the composition,or as coatings over the pellet or granule.

The kind of materials useful for this purpose can be, but are notlimited to, cellulose acetate pthalate, Eudragit L, and other pthalatesalts of cellulose derivatives.

These materials can be present in concentrations from 4-20% (W/W).

Sustained Release Component

The components in this composition are the same as the immediate releasecomponent, but with additional polymers integrated into the composition,or as coatings over the pellet or granule.

The kind of materials useful for this purpose can be, but are notlimited to, ethylcellulose, hydroxypropylmethylcellulose,hydroxypropylcellulose, hydroxyethylcellulose, carboxymethylcellulose,methylcellulose, nitrocellulose, Eudragit R, and Eudragit RL, Carbopol,or polyethylene glycols with molecular weights in excess of 8,000daltons.

These materials can be present in concentrations from 4-20% (W/W).

As hereinabove indicated, the units comprising the antibioticcomposition of the present invention can be in the form of discretepellets or particles contained in the capsule, or particles embedded ina tablet or suspended in a liquid suspension.

The antibiotic composition of the present invention may be administered,for example, by any of the following routes of administration:sublingual, transmucosal, transdermal, parenteral, etc., and preferablyis administered orally. The composition includes a therapeuticallyeffective amount of the antibiotic, which amount will vary with theantibiotic to be used, the disease or infection to be treated, and thenumber of times that the composition is to be delivered in a day. Thecomposition is administered to a host in an amount effective fortreating a bacterial infection.

This system will be especially useful in extending the practialtherapeutic activity for antibiotics with elimination half lives of lessthan 20 hours and more particularly with elimination half-lives of lessthan 12 hours, and will be particularly useful for those drugs withhalf-lives of 2-10 hours. The following are examples of some antibioticswith half-lives of about 1 to 12 hours: Cefadroxil, cefazolin,cephalexin, cephalothin, cephapirin, cephacelor, cephprozil, cephadrine,cefamandole, cefonicid, ceforanide, cefuroxime, cefixime, cefoperazone,cefotaxime, cefpodoxime, ceftaxidime, ceftibuten, ceftizoxime,ceftriaxone, cefepime, cefmetazole, cefotetan, cefoxitin, loracarbef,imipenem, erythromycin (and erythromycin salts such as estolate,ethylsuccinate, gluceptate, lactobionate, stearate), azithromycin,clarithromycoin, dirithromycin, troleanomycin, penicillin V, peniciliinsalts, and complexes, methicillin, nafcillin, oxacillin, cloxacillin,dicloxacillin, amoxicillin, amoxicillin and clavulanate potassium,ampicillin, bacampicillin, carbenicillin indanyl sodium (and other saltsof carbenicillin) mezlocillin, piperacillin, piperacillin andtaxobactam, ticarcillin, ticarcillin and clavulanate potassium,clindamycin, vancomycin, novobiocin, aminosalicylic acid, capreomycin,cycloserine, ethambutol HCl and other salts, ethionamide, and isoniazid,ciprofloxacin, levofloxacin, lomefloxacin, nalidixic acid, norfloxacin,ofloxacin, sparfloxacin, sulfacytine, suflamerazine, sulfamethazine,sulfamethixole, sulfasalazine, sulfisoxazole, sulfapyrizine,sulfadiazine, sulfmethoxazole, sulfapyridine, metronidazole,methenamine, fosfomycin, nitrofurantoin, trimethoprim, clofazimine,co-triamoxazole, pentamidine, and trimetrexate.

The invention will be further described with respect to the followingexamples; however, the scope of the invention is not limited thereby.All percentages in this specification, unless otherwise specified, areby weight.

EXAMPLES

Immediate Release Component

Formulate the composition by mixing the ingredients in a suitablepharmaceutical mixer or granulator such as a planetary mixer, high-sheargranulator, fluid bed granulator, or extruder, in the presence of wateror other solvent, or in a dry blend. If water or other solvent was used,dry the blend in a suitable pharmaceutical drier, such as a vacuum overor forced-air oven. The product may be sieved or granulated, andcompressed using a suitable tablet press, such as a rotary tablet press.

Ingredient Conc. (% W/W) Example 1: Amoxicillin 65% (W/W)Microcrystalline cellulose 20 Povidone 10 Croscarmellose sodium  5Example 2: Amoxicillin 55% (W/W) Microcrystalline cellulose 25 Povidone10 Croscarmellose sodium 10 Example 3: Amoxicillin 65% (W/W)Microcrystalline cellulose 20 Hydroxypropylcellulose 10 Croscarmellosesodium  5 Example 4: Amoxicillin 75% (W/W) Polyethylene glycol 4000 10Polyethylene glycol 2000 10 Hydroxypropylcellulose  5 Example 5:Amoxicillin 75% (W/W) Polyethylene glycol 8000 20 Polyvinylpyrrolidone 5 Example 6: Clarithromycin 65% (W/W) Microcrystalline cellulose 20Hydroxypropylcellulose 10 Croscarmellose sodium  5 Example 7:Clarithromycin 75% (W/W) Microcrystalline cellulose 15Hydroxypropylcellulose  5 Croscarmellose sodium  5 Example 8:Clarithromycin 75% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol2000 10 Hydroxypropylcellulose  5 Example 9: Clarithromycin 75% (W/W)Polyethylene glycol 8000 20 Polyvinylpyrrolidone  5 Example 10:Ciprofloxacin 65% (W/W) Microcrystalline cellulose 20Hydroxypropylcellulose 10 Croscarmellose sodium  5 Example 11:Ciprofloxacin 75% (W/W) Microcrystalline cellulose 15Hydroxypropylcellulose  5 Croscarmellose sodium  5 Example 12:Ciprofloxacin 75% (W/W) Polyethylene glycol 4000 10 Polytheylene glycol2000 10 Hydroxypropylcellulose  5 Example 13: Cirpofloxacin 75% (W/W)Polyethylene glycol 8000 20 Polyvinylpyrrolidone  5 Example 14:Ceftibuten 75% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol2000 10 Hydroxypropylcellulose  5 Example 15: Ceftibuten 75% (W/W)Polyethylene Glycol 4000 20 Polyvinylpyrrolidone  5

Non-pH Sensitive Delayed Release Component

Formulate the composition by mixing the ingredients in a suitablepharmaceutical mixer or granulator such as a planetary mixer, high-sheargranulator, fluid bed granulator, or extruder, in the presence of wateror other solvent, or in a hot melt process. If water or other solventwas used, dry the blend in a suitable pharmaceutical drier, such as avacuum over or forced-air oven. Allow the product to cool, the productmay be sieved or granulated, and compressed using a suitable tabletpress, such as a rotary tablet press.

Ingredient Conc. (% W/W) Example 16: Amoxicillin 65% (W/W)Microcrystalline cellulose 20 Polyox 10 Croscarmellose sodium  5 Example17: Amoxicillin 55% (W/W) Microcrystalline cellulose 25 Polyox 10Glyceryl monooleate 10 Example 18: Amoxicillin 65% (W/W) Polyox 20Hydroxypropylcellulose 10 Croscarmellose sodium  5 Example 19:Clarithromycin 70% (W/W) Polyox 20 Hydroxypropylcellulose  5Croscarmellose sodium  5

Enteric Release Component

Formulate the ingredients by mixing the ingredients in a suitablepharmaceutical mixer or granulator such as a planetary mixer, high-sheargranulator, fluid bed granulator, or extruder, in the presence of wateror other solvent, or in a hot melt process. If water or other solventwas used, dry the blend in a suitable pharmaceutical drier, such as avacuum over or forced-air oven. Allow the product to cool, the productmay be sieved or granulated, and compressed using a suitable tabletpress, such as a rotary tablet press.

Ingredient Conc. (% W/W) \Example 20: Amoxicillin 65% (W/W)Microcrystalline cellulose 20 Cellulose Acetate Pthalate 15 Example 21:Amoxicillin 55% (W/W) Microcrystalline cellulose 25 Cellulose AcetatePthalate 10 Hydroxypropylmethylcellulose 10 Example 22: Amoxicillin 65%(W/W) Polyox 20 Hydroxypropylcellulose pthalate 10 Eudragit L30D  5Example 23: Amoxicillin 40% (W/W) Microcrystalline Cellulose 40Cellulose Acetate Pthalate 10 Example 24: Clarithromycin 70% (W/W)Hydroxypropylcellulose pthalate 15 Croscarmellose sodium 10 Example 25:Clarithromycin 75% (W/W) Polyethylene glycol 2000 10 Eudragit E 30D 15Example 26: Clarithromycin 40% (W/W) Lactose 50 Eudgragit L 30D 10Example 27: Ciprofloxacin 65% (W/W) Microcrystalline Cellulose 20Eudgragit L 30D 10 Example 28: Ciprofloxacin 75% (W/W) MicrocrystallineCellulose 15 Hydroxypropylcellulose pthalate 10 Example 29:Ciprofloxacin 80% (W/W) Lactose 10 Eudragit L 30D 10 Example 30:Ciprofloxacin 70% (W/W) Polyethylene glycol 4000 20 Cellulose acetatepthalate 10 Example 31: Ceftibuten 60% (W/W) Polyethylene glycol 2000 10Lactose 20 Eudragit L 30D 10 Example 32: Ceftibuten 70% (W/W)Microcrystalline cellulose 20 Cellulose acetate pthalate 10

Sustained Release Component

Formulate the composition by mixing the ingredients in a suitablepharmaceutical mixer or granulator such as a planetary mixer, high-sheargranulator, fluid bed granulator, or extruder, in the presence of wateror other solvent, or in a hot melt process. If water or other solventwas used, dry the blend in a suitable pharmaceutical drier, such as avacuum over or forced-air oven. Allow the product to cool, the productmay be sieved or granulated, and compressed using a suitable tabletpress, such as a rotary tablet press.

Ingredient Conc. (% W/W) Example 33: Amoxicillin 65% (W/W)Ethylcellulose 20 Polyox 10 Hydroxypropylmethylcellulose 5 Example 34:Amoxicillin 55% (W/W) Lactose 25 Polyox 10 Glyceryl monooleate 10Example 35: Amoxicillin 70% (W/W) Polyox 20 Hydroxypropylcellulose 10Example 36: Clarithromycin 75% (W/W) Lactose 15 Hydroxypropylcellulose 5 Ethylcellulose  5 Example 37: Clarithromycin 75% (W/W) Polyethyleneglycol 4000 10 Lactose 10 Eudragit RL 30D  5 Example 38: Clarithromycin80% (W/W) Polyethylene glycol 8000 10 Hydroxypropylmethylcellulose  5Eudgragit RS 30D  5 Example 39: Ciprofloxacin 75% (W/W)Hydroxyethylcellulose 10 Polyethylene glycol 4000 10Hydroxypropylcellulose  5 Example 40: Ciprofloxacin 75% (W/W) Lactose 10Povidone (PVP) 10 Polyethylene glycol 2000  5 Example 41: Ceftibuten 75%(W/W) Polyethylene glycol 4000 10 Povidone (PVP) 10Hydroxypropylcellulose  5 Example 42: Ceftibuten 75% (W/W) Lactose 15Polyethylene glycol 4000  5 Polyvinylpyrrolidone  5

Three Pulses

Example 43 1. Metronidazole Matrix Pellet Formulation and PreparationProcedure

(Immediate Release)

A. Pellet Formulation

The composition of the metronidazole matrix pellets provided in Table 1.

TABLE 1 Composition of Metronidazole Pellets Component Percentage (%)Metronidazole 50 Avicel PH 101 20 Lactose 20 PVP K29/32* 10 PurifiedWater Total 100 *PVP K29/32 was added as a 20% w/w aqueous solutionduring wet massing.

B. Preparation Procedure for Metronidazole Matrix Pellets

1.2.1 Blend metronidazole and Avicel® PH 101 using a Robot Coupe highshear granulator.

1.2.2 Add 20% Povidone K29/32 binder solution slowly into the powderblend under continuous mixing.

1.2.3 Extrude the wet mass using an LCI Bench Top Granulator. Thediameter of the screen of the Bench Top Granulator was 1.0 mm.

1.2.4 Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.

1.2.5 Dry the spheronized pellets at 50° C. overnight.

1.2.6 Pellets between 16 and 30 Mesh were collected for furtherprocessing.

1.3 Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion

A. Dispersion Formulation

The composition of the aqueous Eudragit L30D-55 dispersion applied tothe metronidazole matrix pellets is provided below in Table 2.

TABLE 2 Eudragit ® L 30 D-55 Aqueous Coating Dispersion ComponentPercentage (%) Eudragit ® L 30 D-55 55.0 Triethyl Citrate 1.6 Talc 8.0Purified Water 37.4 Solids Content 25.5 Polymer Content 15.9

B. Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion

1.3.1 Suspend triethyl citrate and talc in deionized water.

1.3.2 The TEC/talc suspension is then homogenized using a PowerGen 700high shear mixer.

1.3.3 Add the TEC/talc suspension slowly to the Eudragit® L 30 D-55latex dispersion while stirring.

1.3.4 Allow the coating dispersion to stir for one hour prior toapplication onto the metronidazole matrix pellets.

1.4 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion

A. Dispersion Formulation

The composition of the aqueous Eudragit® S 100 dispersion applied to themetronidazole matrix pellets is provided below in Table 3.

TABLE 3 Eudragit ® S 100 Aqueous Coating Dispersion Component Percentage(%) Part A Eudragit ® S 100 12.0 1 N Ammonium Hydroxide 6.1 TriethylCitrate 6.0 Purified Water 65.9 Part B Talc 2.0 Purified Water 8.0 SolidContent 20.0 Polymer Content 12.0

B. Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion

Part I

(i) Dispense Eudragit® S 100 powder in deionized water with stirring.

(ii) Add ammonium hydroxide solution drop-wise into the dispersion withstirring.

(iii) Allow the partially neutralized dispersion to stir for 60 minutes.

(iv) Add triethyl citrate drop-wise into the dispersion with stirring.Stir for about 2 hours prior to the addition of Part B.

Part II

(i) Disperse talc in the required amount of water

(ii) Homogenize the dispersion using a PowerGen 700D high shear mixer.

(iii) Part B is then added slowly to the polymer dispersion in Part Awith a mild stirring.

1.5 Coating Conditions for the Application of Aqueous CoatingDispersions

The following coating parameters were used to coat matrix pellets witheach of the Eudragit® L 30 D-55 and Eudragit® S 100 aqueous filmcoating.

Coating Equipment STREA 1 ™ Table Top Laboratory Fluid Bed Coater Spraynozzle diameter 1.0 mm Material Charge 300 gram Inlet Air Temperature 40to 45° C. Outlet Air Temperature 30 to 33° C. Atomization Air Pressure1.8 Bar Pump Rate 2 gram per minute

(i) Coat matrix pellets with L30 D-55 dispersion such that you apply 12%coat weight gain to the pellets.

(ii) Coat matrix pellets with S100 dispersion such that you apply 20%coat weight gain to the pellets.

1.6 Encapsulation of the Metronidazole Pellets

Pellets are filled into size 00 hard gelatin capsules at a ratio of30%:30%:40%:

Immediate-release matrix pellets uncoated, L30 D-55 coated pellets andS100 coated pellets respectively.

The capsule is filled with the three different pellets to achieve atotal dose of 375 mg/capsule.

Three Pulses

Example 44 Amoxicillin Pellet Formulation and Preparation Procedure

44.1 Pellet Formulations for Subsequent Coating

The composition of the Amoxicillin trihydrate matrix pellets provided inTable 4.

TABLE 4 Composition of Amoxicillin Matrix Pellets Component Percentage(%) Amoxicillin Trihydrate powder 92 Avicel PH 101 7.0 Hydroxypropylmethylcellulose, NF* 1.0 Total 100 *Hydroxypropyl methylcellulose wasadded as a 2.9% w/w aqueous solution during wet massing.

44.2 Preparation Procedure for Amoxicillin Matrix Pellets

44.2.1 Blend Amoxicillin and Avicel® PH 101 using a low shear blender.

44.2.2 Add the hydroxypropyl methylcellulose binder solution slowly intothe powder blend under continuous mixing.

44.2.3 Extrude the wet mass using an LCI Bench Top Granulator. Thediameter of the screen of the Bench Top Granulator is 0.8 mm.

44.2.4 Spheronize the extrudate using a QJ-230 Spheronizer using a smallcross section plate.

44.2.5 Dry the spheronized pellets at 60° C. using a fluid bed dryeruntil the exhaust temperature reaches 40° C.

44.2.6 Pellets between 20 and 40 Mesh were collected for furtherprocessing.

44.3 Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion

44.3.1 Dispersion Formulation

The composition of the aqueous Eudragit L30D-55 dispersion applied tothe amoxicillin matrix pellets is provided below in Table 5.

TABLE 5 Eudragit ® L 30 D-55 Aqueous Coating Dispersion ComponentPercentage (%) Eudragit ® L 30 D-55 41.6 Triethyl Citrate 2.5 Talc 5.0Purified Water 50.9 Solids Content 20.0 Polymer Content 12.5

44.4 Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion

44.4.1 Suspend triethyl citrate and talc in deionized water.

44.4.2 The TEC/talc suspension is mixed using laboratory mixer.

44.4.3 Add the TEC/talc suspension from slowly to the Eudragit® L 30D-55 latex dispersion while stirring.

44.4.4 Allow the coating dispersion to stir for one hour prior toapplication onto the amoxicillin matrix pellets.

44.5 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion

44.5.1 Dispersion Formulation

The composition of the aqueous Eudragit® S 100 dispersion applied to theAmoxicillin matrix pellets is provided below in Table 6.

TABLE 6 Eudragit ® S 100 Aqueous Coating Dispersion Component Percentage(%) Part A Eudragit ® S 100 10.0 1 N Ammonium Hydroxide 5.1 TriethylCitrate 5.0 Water 64.9 Part B Talc 5.0 Water 10.0 Solid Content 25.0Polymer Content 10.0

44.6 Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion

Part A:

44.6.1 Dispense Eudragit® S 100 powder in deionized water with stirring.

44.6.2 Add ammonium hydroxide solution drop-wise into the dispersionwith stirring.

44.6.3 Allow the partially neutralized dispersion to stir for 60minutes.

44.6.4 Add triethyl citrate drop-wise into the dispersion with stirringand let stir overnight prior to the addition of Part B.

Part B:

44.6.5 Disperse talc in the required amount of water

44.6.6 Stir the dispersion using an overhead laboratory mixer.

44.6.7 Part B is then added slowly to the polymer dispersion in Part Awith a mild stirring.

44.7 Coating Conditions for the Application of Aqueous CoatingDispersions

The following coating parameters were used for both the Eudragit® L 30D-55 and Eudragit® S 100 aqueous film coating processes.

Coating Equipment STREA 1 ™ Table Top Laboratory Fluid Bed Coater Spraynozzle diameter 1.0 mm Material Charge 300 gram Inlet Air Temperature 40to 45° C. Outlet Air Temperature 30 to 33° C. Atomization Air Pressure1.8 Bar Pump Rate 2-6 gram per minute

44.7.1 Coat matrix pellets with L30 D-55 dispersion such that you apply20% coat weight gain to the pellets.

44.7.2 Coat matrix pellets with S100 dispersion such that you apply 37%coat weight gain to the pellets.

44.8 Preparation of Amoxicillin Granulation (Immediate ReleaseComponent) for tabletting

TABLE 7 Composition of Amoxicillin Granulation Component Percentage (%)Amoxicillin Trihydrate powder 92   Avicel PH 101 7.0 Hydroxypropylmethylcellulose, NF* 1.0 Total 100    *Hydroxypropyl methylcellulose wasadded as a 2.9% w/w aqueous solution during wet massing.

44.8.1 Blend Amoxicillin and Avicel® PH 101 using a low shear blender.

44.8.2 Add the hydroxypropyl methylcellulose binder solution slowly intothe powder blend under continuous mixing.

44.8.3 Dry the granulation at 60° C. using a fluid bed dryer until theexhaust temperature reaches 40° C.

44.8.4 Granules between 20 and 40 Mesh are collected for furtherprocessing.

44.9 Tabletting of the Amoxicillin Pellets

TABLE 8 Composition of Amoxicillin Tablets Component Percentage (%)Amoxicillin granules 32.5 Avicel PH 200 5.0 Amoxicillin L30D-55 coatedpellets 30 Amoxicillin S100 coated pellets 30 Colloidal silicon dioxide1.5 Magnesium stearate 1.0 Total 100

44.9.1 Blend the Amoxicillin granules, Avicel PH-200, Amoxicillinpellets and colloidal silicon dioxide for 15 minutes in a tumbleblender.

44.9.2 Add the magnesium stearate to the blender, and blend for 5minutes.

44.9.3 Compress the blend on a rotary tablet press.

44.9.4 The fill weight should be adjusted to achieve a 500 mg dosetablet.

Three Pulses

Example 45 Clarithromycin Pellet Formulation and Preparation Procedure

45.1 Pellet Formulation

The composition of the clarithromycin matrix pellets provided in Table1.

TABLE 9 Composition of Clarithromycin Pellets Component Percentage (%)Clarithromycin 50.6 Lactose monohydrate, spray dried 32.1 Silicifiedmicrocrystalline cellulose 14.6 Polyoxyl 35 Castor Oil* 1.7Hydroxypropyl methylcellulose* 1.0 Total 100 *Hydroxypropylmethylcellulose and Polyoxyl 35 were added as an 8.7% w/w aqueoussolution during wet massing.

45.2 Preparation Procedure for Clarithromycin Matrix Pellets

45.2.1 Blend clarithromrycin, silicified microcrystalline cellulose andlactose monohydrate using a Robot Coupe high shear granulator.

45.2.2 Prepare the binder solution by adding the Polyoxyl to thepurified water while stirring. After that is mixed, slowly add thehydroxypropyl methylcellulose and continue to stir until a solution isachieved.

45.2.3 Add binder solution slowly into the powder blend under continuousmixing.

45.2.4 Granulate the powders in the high shear granulator with thebinder solution.

45.2.5 Extrude the wet mass using an LCI Bench Top Granulator. Thediameter of the screen of the Bench Top Granulator was 1.2 mm.

45.2.6 Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.

45.2.7 Dry the spheronized pellets at 50° C. overnight.

45.2.8 Pellets between 18 and 30 Mesh were collected for furtherprocessing.

45.3 Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion

45.3.1 Dispersion Formulation

The composition of the aqueous Eudragit L30D-55 dispersion applied tothe clarithromycin matrix pellets is provided below in Table 10.

TABLE 10 Eudragit ® L 30 D-55 Aqueous Coating Dispersion ComponentPercentage (%) Eudragit ® L 30 D-55 40.4 Triethyl Citrate 1.8 Talc 6.1Water 51.7 Solids Content 20.0 Polymer Content 12.1

45.4 Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion

45.4.1 Suspend triethyl citrate and talc in deionized water.

45.4.2 The TEC/talc suspension is then homogenized using a PowerGen 700high shear mixer.

45.4.3 Add the suspension from 4.2.2 slowly to the Eudragit® L 30 D-55latex dispersion while stirring.

45.4.4 Allow the coating dispersion to stir for one hour prior toapplication onto the clarithromycin matrix pellets.

45.5 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion

45.5.1 Dispersion Formulation

The composition of the aqueous Eudragit® S 100 dispersion applied to theclarithromycin matrix pellets is provided below in Table 11.

TABLE 11 Eudragit ® S 100 Aqueous Coating Dispersion ComponentPercentage (%) Part A Eudragit ® S 100 10.0 1 N Ammonium Hydroxide 5.1Triethyl Citrate 5.0 Water 64.9 Part B Talc 5.0 Water 10.0 Solid Content25.0 Polymer Content 10.0

45.6 Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion

Part A:

45.6.1 Dispense Eudragit® S 100 powder in deionized water with stirring.

45.6.2 Add ammonium hydroxide solution drop-wise into the dispersionwith stirring.

45.6.3 Allow the partially neutralized dispersion to stir for 60 minutes

45.6.4 Add the triethyl citrate drop-wise to the dispersion and stir for60 minutes prior to the addition of Part B.

Part B:

45.6.5 Disperse talc in the required amount of water

45.6.6 Homogenize the dispersion using a PowerGen 700D high shear mixer.

45.6.7 Part B is then added slowly to the polymer dispersion in Part Awith a mild stirring.

45.7 Coating Conditions for the Application of Aqueous CoatingDispersions

The following coating parameters were used for coating the matrixpellets with each of the Eudragit® L 30 D-55 and Eudragit® S 100 aqueousfilm coating.

Coating Equipment STREA 1 ™ Table Top Laboratory Fluid Bed Coater Spraynozzle diameter 1.0 mm Material Charge 300 gram Inlet Air Temperature 40to 45° C. Outlet Air Temperature 30 to 33° C. Atomization Air Pressure1.6 Bar Pump Rate 2 gram per minute

45.7.1 Coat matrix pellets with L30 D-55 dispersion such that you apply20% coat weight gain to the pellets.

45.7.2 Coat matrix pellets with S100 dispersion such that you apply 37%coat weight gain to the pellets.

4. Capsules were filled with the uncoated pellets, the L30D-55 coatedpellets and S100 coated pellets in weight percentages of 30%:30%:40%,respectively to provide 250 mg. capsules.

Four Pulses

Example 46 1 Metronidazole Matrix Pellet Formulation and PreparationProcedure

46.1 Pellet Formulation

The composition of the metronidazole matrix pellets provided in Table12.

TABLE 12 Composition of Metronidazole Pellets Component Percentage (%)Metronidazole 50 Avicel PH 101 20 Lactose 20 PVP K29/32* 10 PurifiedWater Total 100 *PVP K29/32 was added as a 20% w/w aqueous solutionduring wet massing.

46.2 Preparation Procedure for Metronidazole Matrix Pellets

46.2.1 Blend metronidazole and Avicel® PH 101 using a Robot Coupe highshear granulator.

46.2.2 Add 20% Povidone K29/32 binder solution slowly into the powderblend under continuous mixing.

46.2.3 Extrude the wet mass using an LCI Bench Top Granulator. Thediameter of the screen of the Bench Top Granulator was 1.0 mm.

46.2.4 Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.

46.2.5 Dry the spheronized pellets at 50° C. overnight.

46.2.6 Pellets between 16 and 30 Mesh were collected for furtherprocessing.

46.3 Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion

46.3.1 Dispersion Formulation

The composition of the aqueous Eudragit L30D-55 dispersion applied tothe metronidazole matrix pellets is provided below in Table 13.

TABLE 13 Eudragit ® L 30 D-55 Aqueous Coating Dispersion ComponentPercentage (%) Eudragit ® L 30 D-55 55.0 Triethyl Citrate 1.6 Talc 8.0Purified Water 37.4 Solids Content 25.5 Polymer Content 15.9

46.4 Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion

46.4.1 Suspend triethyl citrate and talc in deionized water.

46.4.2 The TEC/talc suspension is then homogenized using a PowerGen 700high shear mixer.

46.4.3 Add the TEC/talc suspension slowly to the Eudragit® L 30 D-55latex dispersion while stirring.

46.4.4 Allow the coating dispersion to stir for one hour prior toapplication onto the metronidazole matrix pellets.

46.5 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion

46.5.1 Dispersion Formulation

The composition of the aqueous Eudragit® S 100 dispersion applied to themetronidazole matrix pellets is provided below in Table 14.

TABLE 14 Eudragit ® S 100 Aqueous Coating Dispersion ComponentPercentage (%) Part A Eudragit ® S 100 12.0 1 N Ammonium Hydroxide 6.1Triethyl Citrate 6.0 Purified Water 65.9 Part B Talc 2.0 Purified Water8.0 Solid Content 20.0 Polymer Content 12.0

46.6 Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion

Part A:

46.6.1 Dispense Eudragit® S 100 powder in deionized water with stirring.

46.6.2 Add ammonium hydroxide solution drop-wise into the dispersionwith stirring.

46.6.3 Allow the partially neutralized dispersion to stir for 60minutes.

46.6.4 Add triethyl citrate drop-wise into the dispersion with stirring.Stir for about 2 hours prior to the addition of Part B.

Part B:

46.6.5 Disperse talc in the required amount of water

46.6.6 Homogenize the dispersion using a PowerGen 700D high shear mixer.

46.6.7 Part B is then added slowly to the polymer dispersion in Part Awith a mild stirring.

46.7 Coating Conditions for the Application of Aqueous CoatingDispersions

The following coating parameters were used for coating with each of theEudragit® L 30 D-55 and Eudragit® S 100 aqueous film coatings.

Coating Equipment STREA 1 ™ Table Top Laboratory Fluid Bed Coater Spraynozzle diameter 1.0 mm Material Charge 300 gram Inlet Air Temperature 40to 45° C. Outlet Air Temperature 30 to 33° C. Atomization Air Pressure1.8 Bar Pump Rate 2 gram per minute

46.7.1 Coat matrix pellets with L30 D-55 dispersion such that you apply12% coat weight gain to the pellets.

46.7.2 Coat matrix pellets with L30 D-55 dispersion such that you apply30% coat weight gain to the pellets.

46.7.3 Coat matrix pellets with S100 dispersion such that you apply 20%coat weight gain to the pellets.

46.8 Encapsulation of the Metronidazole Pellets

Pellets are filled into size 00 hard gelatin capsules at a ratio of20%:30%:20%:30% Immediate-release matrix pellets (uncoated), L30 D-55coated pellets 12% weight gain, L30D-55 coated pellets 30% weight gainand S100 coated pellets respectively. The capsule is filled with thefour different pellets to achieve a total dose of 375 mg/capsule.

Four Pulses

Example 47 Amoxicillin Pellet Formulation and Preparation Procedure

47.1 Pellet Formulations

The composition of the Amoxicillin trihydrate matrix pellets provided inTable 15.

TABLE 15 Composition of Amoxicillin Matrix Pellets Component Percentage(%) Amoxicillin Trihydrate powder 92 Avicel PH 101 7.0 Hydroxypropylmethylcellulose, NF* 1.0 Total 100 *Hydroxypropyl methylcellulose wasadded as a 2.9% w/w aqueous solution during wet massing.

47.2 Preparation Procedure for Amoxicillin Matrix Pellets

47.2.1 Blend Amoxicillin and Avicel® PH 101 using a low shear blender.

47.2.2 Add the hydroxypropyl methylcellulose binder solution slowly intothe powder blend under continuous mixing.

47.2.3 Extrude the wet mass using an LCI Bench Top Granulator. Thediameter of the screen of the Bench Top Granulator is 0.8 mm.

47.2.4 Spheronize the extrudate using a QJ-230 Spheronizer using a smallcross section plate.

47.2.5 Dry the spheronizied pellets at 60° C. using a fluid bed dryeruntil the exhaust temperature reaches 40° C.

47.2.6 Pellets between 20 and 40 Mesh were collected for furtherprocessing.

47.3 Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion

47.3.1 Dispersion Formulation

The composition of the aqueous Eudragit L30D-55 dispersion applied tothe amoxicillin matrix pellets is provided below in Table 16.

TABLE 16 Eudragit ® L 30 D-55 Aqueous Coating Dispersion ComponentPercentage (%) Eudragit ® L 30 D-55 41.6 Triethyl Citrate 2.5 Talc 5.0Purified Water 50.9 Solids Content 20.0 Polymer Content 12.5

47.4 Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion

47.4.1 Suspend triethyl citrate and talc in deionized water.

47.4.2 The TEC/talc suspension is mixed using laboratory mixer.

47.4.3 Add the TEC/talc suspension from slowly to the Eudragit® L 30D-55 latex dispersion while stirring.

47.4.4 Allow the coating dispersion to stir for one hour prior toapplication onto the amoxicillin matrix pellets.

47.5 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion

47.6 Dispersion Formulation

The composition of the aqueous Eudragit® S 100 dispersion applied to theAmoxicillin matrix pellets is provided below in Table 17.

TABLE 17 Eudragit ® S 100 Aqueous Coating Dispersion ComponentPercentage (%) Part A Eudragit ® S 100 10.0 1 N Ammonium Hydroxide 5.1Triethyl Citrate 5.0 Water 64.9 Part B Talc 2.0 Water 10.0 Solid Content25.0 Polymer Content 10.0

47.7 Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion

Part A:

47.7.1 Dispense Eudragit® S 100 powder in deionized water with stirring.

47.7.2 Add ammonium hydroxide solution drop-wise into the dispersionwith stirring.

47.7.3 Allow the partially neutralized dispersion to stir for 60minutes.

47.7.4 Add triethyl citrate drop-wise into the dispersion with stirringand let stir overnight prior to the addition of Part B.

Part B:

47.7.5 Disperse talc in the required amount of water

47.7.6 Stir the dispersion using an overhead laboratory mixer.

47.7.7 Part B is then added slowly to the polymer dispersion in Part Awith a mild stirring.

47.8 Preparation of Aquacoat Coating Dispersion

47.8.1 Dispersion Formulation

The composition of the aqueous Aquacoat dispersion applied toAmoxicillin L30 D-55 coated pellets is provided below in Table 18.

TABLE 18 Component Percentage (%) Aquacoat ECD 79.3 Hydroxypropylmethylcellulose 15.9 Dibutyl Sebacate 4.8 Purified Water (300 g)

47.8.1.1 Prepare Hydroxypropyl methylcellulose (Methocel E15) solutionby dispersing in water with continuous stirring.

47.8.1.2 Add Aquacoat and dibutyl sebacate to the dispersion withstirring and continue to stir overnight.

47.9 Coating Conditions for the Application of Aqueous CoatingDispersions

The following coating parameters were used for coating with each of theEudragit® L 30 D-55 and Eudragit® S 100 aqueous film coatings.

Coating Equipment STREA 1 ™ Table Top Laboratory Fluid Bed Coater Spraynozzle diameter 1.0 mm Material Charge 300 gram Inlet Air Temperature 40to 45° C. Outlet Air Temperature 30 to 33° C. Atomization Air Pressure1.8 Bar Pump Rate 2-6 gram per minute

47.9.1 Coat Amoxicillin matrix pellets with L30 D-55 dispersim toachieve a 20% coat weight gain.

47.9.2 Coat another batch of Amoxicillin matrix pellets with L30 D-55dispersion to achieve a 20% weight gain. Coat the L30 D-55 pellets withthe Aquacoat Dispersion to achieve a 10% coat weight gain.

47.9.3 Coat Amoxicillin matrix pellets with S100 dispersion to achieve a37% coat weight gain.

47.10 Preparation of Amoxicillin Granulation for Tabletting

TABLE 19 Composition of Amoxicillin Granulation (Immediate Release)Component Percentage (%) Amoxicillin Trihydrate powder 92 Avicel PH 1017.0 Hydroxypropyl methylcellulose, NF* 1.0 Total 100 *Hydroxypropylmethylcellulose was added as a 2.9% w/w aqueous solution during wetmassing.

47.10.1 Blend Amoxicillin and Avicel® PH 101 using a low shear blender.

47.10.2 Add the hydroxypropyl methylcellulose binder solution slowlyinto the powder blend under continuous mixing.

47.10.3 Dry the granulation at 60° C. using a fluid bed dryer until theexhaust temperature reaches 40° C.

47.10.4 Granules between 20 and 40 Mesh are collected for furtherprocessing.

47.11 Tabletting of the Amoxicillin Pellets

TABLE 20 Composition of Amoxicillin Tablets Component Percentage (%)Amoxicillin granules 32.5 Avicel PH 200 5.0 Amoxicillin L30D-55 coatedpellets 20 Amoxicillin Aquacoated pellets 20 Amoxicillin S100 coatedpellets 20 Colloidal silicon dioxide 1.5 Magnesium stearate 1.0 Total100

47.11.1 Blend the Amoxicillin granules, Avicel PH-200, Amoxicillinpellets and colloidal silicon dioxide for 15 minutes in a tumbleblender.

47.11.2 Add the magnesium stearate to the blender, and blend for 5minutes.

47.11.3 Compress the blend on a rotary tablet press.

47.11.4 The fill weight should be adjusted to achieve a 500 mg dosetablet.

Four Pulses

Example 48 Clarithromycin Pellet Formulation and Preparation Procedure

48.1 Pellet Formulation

The composition of the clarithromycin matrix pellets provided in Table21.

TABLE 21 Composition of Clarithromycin Pellets Component Percentage (%)Clarithromycin 50.6 Lactose monohydrate, spray dried 32.1 Silicifiedmicrocrystalline cellulose 14.6 Polyoxyl 35 Castor Oil* 1.7Hydroxypropyl methylcellulose* 1.0 Total 100 *Hydroxypropylmethylcellulose and Polyoxyl 35 were added as an 8.7% w/w aqueoussolution during wet massing.

48.2 Preparation Procedure for Clarithromycin Matrix Pellets

48.2.1 Blend clarithromycin, silicified microcrystalline cellulose andlactose monohydrate using a Robot Coupe high shear granulator.

48.2.2 Prepare the binder solution by adding the Polyoxyl to thepurified water while stirring. After that is mixed, slowly add thehydroxypropyl methylcellulose and continue to stir until a solution isachieved.

48.2.3 Add binder solution slowly into the powder blend under continuousmixing.

48.2.4 Granulate the powders in the high shear granulator with thebinder solution.

48.2.5 Extrude the wet mass using an LCI Bench Top Granulator. Thediameter of the screen of the Bench Top Granulator was 1.2 mm.

48.2.6 Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.

48.2.7 Dry the spheronized pellets at 50° C. overnight.

48.2.8 Pellets between 18 and 30 Mesh were collected for furtherprocessing.

48.3 Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion

48.3.1 Dispersion Formulation

The composition of the aqueous Eudragit L30D-55 dispersion applied tothe clarithromycin matrix pellets is provided below in Table 22.

TABLE 22 Eudragit ® L 30 D-55 Aqueous Coating Dispersion ComponentPercentage (%) Eudragit ® L 30 D-55 40.4 Triethyl Citrate 1.8 Talc 6.1Water 51.7 Solids Content 20.0 Polymer Content 12.1

48.4 Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion

48.4.1 Suspend triethyl citrate and talc in deionized water.

48.4.2 The TEC/talc suspension is then homogenized using a PowerGen 700high shear mixer.

48.4.3 Add the suspension from 4.2.2 slowly to the Eudragit® L 30 D-55latex dispersion while stirring.

48.4.4 Allow the coating dispersion to stir for one hour prior toapplication onto the clarithromycin matrix pellets.

48.5. Preparation of an Eudragit® S 100 Aqueous Coating Dispersion

48.5.1 Dispersion Formulation

The composition of the aqueous Eudragit® S 100 dispersion applied to theclarithromycin matrix pellets is provided below in Table 23.

TABLE 23 Eudragit ® S 100 Aqueous Coating Dispersion ComponentPercentage (%) Part A Eudragit ® S 100 10.0 1 N Ammonium Hydroxide 5.1Triethyl Citrate 5.0 Water 64.9 Part B Talc 5.0 Water 10.0 Solid Content25.0 Polymer Content 10.0

48.6 Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion

Part A:

48.6.1 Dispense Eudragit® S 100 powder in deionized water with stirring.

48.6.2 Add ammonium hydroxide solution drop-wise into the dispersionwith stirring.

48.6.3 Allow the partially neutralized dispersion to stir for 60 minutes

48.6.4 Add the triethyl citrate drop-wise to the dispersion and stir for60 minutes prior to the addition of Part B.

Part B:

48.6.5 Disperse talc in the required amount of water

48.6.6 Homogenize the dispersion using a PowerGen 700D high shear mixer.

48.6.7 Part B is then added slowly to the polymer dispersion in Part Awith a mild stirring.

48.7 Coating Conditions for the Application of Aqueous CoatingDispersions

The following coating parameters were used for coating with each of theEudragit® L 30 D-55 and Eudragit® S 100 aqueous film coatings.

Coating Equipment STREA 1 ™ Table Top Laboratory Fluid Bed Coater Spraynozzle diameter 1.0 mm Material Charge 300 gram Inlet Air Temperature 40to 45° C. Outlet Air Temperature 30 to 33° C. Atomization Air Pressure1.6 Bar Pump Rate 2 gram per minute

48.7.1 Coat matrix pellets with L30 D-55 dispersion such that you apply12% coat weight gain to the pellets.

48.7.2 Coat matrix pellets with L30 D-55 dispersion such that you apply30% coat weight gain to the pellets.

48.7.3 Coat matrix pellets with S100 dispersion such that you apply 37%coat weight gain to the pellets.

48.8 Encapsulation of the Clarithromycin Pellets

Pellets are filled into size 00 hard gelatin capsules at a ratio of20%:30%:20%:30% Immediate-release matrix pellets (uncoated), L30 D-55coated pellets 12% weight gain, L30D-55 coated pellets 30% weight gainand S100 coated pellets respectively.

The capsule is filled with the four different pellets to achieve a totaldose of 250 mg/capsule.

Four Pulses

Example 49 Clarithromycin Pellet Formulation and Preparation Procedure

Pellet Formulation

The composition of the clarithromycin pellets provided in Table 24.

TABLE 24 Composition of Clarithromycin Pellets Component Percentage (%)Clarithromycin 77.0 Lactose monohydrate, spray dried 11.0 Croscarmellosesodium 5.0 Polyoxyl 35 Castor Oil* 5.0 Hydroxypropyl methylcellulose*2.0 Purified water * Total 100 *Removed during processing

Preparation Procedure for Clarithromycin Pellets

Prepare the binder solution by adding the Polyoxyl to the purified waterwhile stirring. After that is mixed, slowly add the hydroxypropylmethylcellulose and continue to stir until a solution is achieved.

Blend clarithromycin, lactose monohydrate, and croscarmellose sodiumusing a Robot Coupe high shear granulator.

Add binder solution slowly into the powder blend under continuousmixing.

Granulate the powders in the high shear granulator with the bindersolution.

Extrude the wet mass using an LCI Bench Top Granulator. The diameter ofthe screen of the Bench Top Granulator was 1.0 mm.

Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.

Dry the spheronized pellets at 50° C. until the moisture level is >3%.

Pellets between 16 and 30 Mesh were collected for further processing.

Clarithromycin Enteric-Release Pellet Formulation and PreparationProcedure

Preparation of an Eudragit® L 30 D-55/Eudragit NE 30D Aqueous CoatingDispersion

Dispersion Formulation

The composition of the aqueous Eudragit L30D-55/Eudragit NE 30D aqueouscoating dispersion applied to the clarithromycin pellets is providedbelow in Table 25.

TABLE 25 Eudragit ® L 30 D-55/Eudragit NE 30D Aqueous Coating DispersionComponent Percentage (%) Eudragit ® L 30D-55 44.4 Eudragit NE 30D 14.8Triethyl Citrate 1.3 Imwitor 900 0.9 Purified Water* 38.6 Solid Content20.6 Polymer Content 16.4 *Removed during processing

Preparation Procedure for an Eudragit® L 30D-55/Eudragit NE 30D AqueousDispersion

Heat purified water to 75-80° C. and then add triethyl citrate (TEC) andImwitor 900. Homogenize dispersion until temperature is less than 55° C.

The TEC/Imwitor 900 dispersion is then stirred until the temperature isless than 35° C.

Add the TEC/Imwitor 900 dispersion to Eudragit L30D-55 latex dispersionand stir for at least 30 minutes.

Add Eudragit NE 30D to the Eudragit L30D/TEC/Imwitor 900 dispersion andstir for at least 10 minutes.

Screen the dispersion through a No. 60 mesh sieve prior to coating.

Continue to stir the dispersion until the coating process is complete.

Coating Conditions for the Application of Eudragit L30D-55/Eudragit NE30D Aqueous

Coating Dispersion

The following coating parameters were used for coating of the Eudragit®L 30 D-55/Eudragit NE30D film coating dispersion.

Coating Equipment STREA 1 ™ Table Top Laboratory Fluid Bed Coater Spraynozzle diameter 1.0 mm Material Charge 300 gram Inlet Air Temperature45° C. Outlet Air Temperature 32 to 35° C. Atomization Air Pressure 1.6Bar Pump Rate 3-4 gram per minute

Coat clarithromycin pellets with Eudragit L30 D-55/Eudragit NE 30D filmcoating dispersion such that you apply 20% coat weight gain to thepellets.

Clarithromycin Delayed Enteric-Release Pellets Formulation andPreparation Procedure

Preparation of an AQOAT AS-HF Aqueous Coating Dispersion

Dispersion Formulation

The composition of the aqueous AQOAT AS-HF aqueous coating dispersionapplied to the clarithromycin pellets is provided below in Table 26.

TABLE 26 AQOAT AS-HF Aqueous Coating Dispersion Component Percentage (%)AQOAT AS-HF 7.0 Triethyl Citrate 2.0 Talc 2.1 Sodium lauryl sulfate 0.2Purified Water* 88.7 Solid Content 11.3 Polymer Content 7.0 *Removedduring processing

Preparation Procedure for an AQOAT AS-HF Aqueous Dispersion

Add triethyl citrate (TEC) to the purified water with stirring.

Add the sodium lauryl sulfate (SLS) to the TEC dispersion with stirringand completely until completely dissolved.

Add the AQOAT to the TEC/SLS dispersion and stir for at least 30minutes.

Add the talc to the AQOAT dispersion and until completely mixed and forat least 30 minutes.

Screen the dispersion through a No. 60 mesh sieve prior to coating.

Continue to stir the dispersion until the coating process is complete.

Coating Conditions for the Application of AQOAT AS-HF Aqueous CoatingDispersion

The following coating parameters were used for coating of the AQOATAS-HF film coating dispersion.

Coating Equipment STREA 1 ™ Table Top Laboratory Fluid Bed Coater Spraynozzle diameter 1.0 mm Material Charge 300 gram Inlet Air Temperature48° C. Outlet Air Temperature 27° C. Atomization Air Pressure 1.6 BarPump Rate 3-4 gram per minute

Coat clarithromycin pellets with AQOAT AS-HF film coating dispersionsuch that you apply 30-35% coat weight gain to the pellets.

Clarithromycin Colonic-Release Pellets Formulation and PreparationProcedure

Preparation of an Eudragit® FS30D Aqueous Coating Dispersion

Dispersion Formulation

The composition of the aqueous Eudragit® FS 30D dispersion applied tothe clarithromycin pellets is provided below in Table 27.

TABLE 27 Eudragit ® FS 30D Aqueous Coating Dispersion ComponentPercentage (%) Eudragit ® FS 30D 54.8 Triethyl Citrate 0.9 Talc 3.3Purified Water* 41.0 Solid Content 20.6 Polymer Content 16.4 *Removedduring processing

Preparation Procedure for an Eudragit® FS 30D Aqueous Dispersion

Disperse triethyl citrate (TEC) in the purified water.

Add the talc in the triethyl citrate dispersion.

Homogenize the dispersion using a homogenizer.

Add slowly the Eudragit® FS 30D dispersion to the talc/TEC dispersionwith stirring.

Continue to stir the coating dispersion until the coating process iscomplete.

Coating Conditions for the Application of Eudragit FS30D Aqueous CoatingDispersion

The following coating parameters were used for coating with each of theEudragit® FS 30 D aqueous film coating.

Coating Equipment STREA 1 ™ Table Top Laboratory Fluid Bed Coater Spraynozzle diameter 1.2 mm Material Charge 300 gram Inlet Air Temperature38° C. Outlet Air Temperature 22° C. Atomization Air Pressure 1.6 BarPump Rate 6 gram per minute

Coat pellets with Eudragit FS 30D coating dispersion dispersion suchthat you apply 30% coat weight gain to the pellets.

Encapsulation of the Clarithromycin Pellets

Pellets are filled into hard gelatin capsules at a ratio of25%:25%:25%:25% Immediate-Release Pellets (uncoated), Eudragit L30D-55/Eudagit NE 30D coated pellets 20% weight gain, AQOAT AS-HF coatedpellets 30-35% weight gain and Eudragit FS 30D coated pelletsrespectively.

The capsule is filled with the four different pellets to achieve a totaldose of 250 mg/capsule.

Tableting of the Clarithromycin Pellets

Clarithromycin Tablet Formula

TABLE 28 Clarithromycin Tablet Component Percentage (%) Eudragit ®L30D/NE 30D coated pellets 20.0 AQOAT AS-HF coated pellets 20.0 EudargitFS 30D coated pellets 20.0 Emcocel 24.5 Clarithromycin 12.5 Povidone K302.0 Magnesium stearate 1.0 Purified water * * Removed during processing

Preparation Procedure for a Clarithromycin Tablet

Blend all the components together except coated pellets and magnesiumstearate for 10 minutes using a granulator.

Granulate the blend with purified water.

Screen the granulate through a No. 16 mesh sieve.

Dry the screened granulate in a fluid bed dryer at 50-60° C. until themoisture level is less than 3%.

Add the dry granulate, coated pellets to a tumble blender and blend for10 minutes.

Add to the blend the magnesium stearate and blend an additional 3minutes.

Compress the blend on a rotary tablet press to achieve a dose of 500 mg.

The present invention is particularly advantageous in that there isprovided an antibiotic product which provides an improvement over twicea day administration of the antibiotic and an improvement over a once aday administration of the antibiotic.

Numerous modification and variations of the present invention arepossible in light of the above teachings and therefore, within the scopeof the appended claims the invention may be practiced otherwise than asparticularly described.

The present invention is particularly advantageous in that there isprovided an antibiotic product which provides an improvement over twicea day administration of the antibiotic and an improvement over a once aday administration of the antibiotic.

Numerous modification and variations of the present invention arepossible in light of the above teachings and therefore, within the scopeof the appended claims the invention may be practiced otherwise than asparticularly described.

What is claimed is:
 1. A once-a-day antibiotic product comprising:first, second, and third dosage forms; each of said dosage formscomprising an erythromyacin and a pharmaceutically acceptable carrier;said first dosage form being an immediate release dosage form; saidsecond and third dosage forms being delayed release dosage forms;wherein each of said first, second, and third dosage forms initiatesrelease of the erythromyacin at different times; wherein Cmax of thetotal erythromyacin released from said product is achieved in less thanabout 12 hours from administration; and wherein said once-a-day productcontains the total dosage of the erythromyacin for a twenty-four hourperiod.
 2. A once-a-day antibiotic product comprising: first, second,and third dosage forms; each of said dosage forms comprisingclarithromycin and a pharmaceutically acceptable carrier; said firstdosage form being an immediate release dosage form; said second andthird dosage forms being delayed release dosage forms; wherein each ofsaid first, second, and third dosage forms initiates release oferythromyacin at different times; wherein Cmax of the totalerythromyacin released from said product is achieved in less than about12 hours from administration; and wherein said once-a-day productcontains the total dosage of erythromyacin for a twenty-four hourperiod.
 3. The product of claim 2, wherein the Cmax for the product isreached no earlier than four hours after administration.
 4. The productof claim 2, wherein the clarithromycin released from the first dosageform reaches a Cmax within from about 0.5 hours to about 2 hours afteradministration of the product.
 5. The product of claim 2, wherein theclarithromycin released from the second dosage form reaches a Cmax in nomore than about 4 hours after administration of the product.
 6. Theproduct of claim 2, wherein the clarithromycin released from the thirddosage form reaches a Cmax within 8 hours after administration of theproduct.
 7. The product of claim 2, wherein the immediate release dosageform contains at least 20% and no more than 50% of the total dosage ofclarithromycin.
 8. The product of claim 2, wherein the product is anoral dosage form.
 9. The product of claim 2, wherein the clarithromycinreleased from the second dosage form reaches a Cmax after Cmax isreached for the clarithromycin released from the first dosage form. 10.The product of claim 2, wherein the clarithromycin released from thethird dosage form reaches a Cmax after Cmax is reached for theclarithromycin released from the second dosage form.
 11. The product ofclaim 2 further comprising a fourth dosage form, said fourth dosage formbeing a delayed release dosage form comprising clarithromycin and apharmaceutically acceptable carrier; and wherein clarithromycin releasedfrom said fourth dosage form reaches a Cmax after Cmax is achieved forclarithromycin released from each of said first, second, and thirddosage forms.
 12. The product of claim 11, wherein the Cmax for theproduct is reached no earlier than four hours after administration. 13.The product of claim 11, wherein the clarithromycin released from thefirst dosage form reaches a Cmax within from about 0.5 hours to about 2hours after administration of the product.
 14. The product of claim 11,wherein the clarithromycin released from the second dosage form reachesa Cmax in no more than about 4 hours after administration of theproduct.
 15. The product of claim 11, wherein the clarithromycinreleased from the third dosage form reaches a Cmax within 8 hours afteradministration of the product.
 16. The product of claim 11, wherein saidsecond dosage form initiates release of clarithromycin before said thirddosage form, wherein said third dosage form initiates release ofclarithromycin before said fourth dosage form, wherein said seconddosage form provides 20% to 35% by weight of the total clarithromycinreleased by said second, third, and fourth dosage forms, wherein saidthird dosage form provides from 20% to 40% by weight of the totalclarithromycin released by said second, third, and fourth dosage forms,and wherein said fourth dosage form provides the remainder of the totalclarithromycin released by said second, third, and fourth dosage forms.17. The product of claim 11, wherein the product is an oral dosage form.18. The product of claim 11, wherein the clarithromycin released fromthe second dosage form reaches a Cmax after Cmax is reached for theclarithromycin released from the first dosage form.
 19. The product ofclaim 11, wherein the clarithromycin released from the third dosage formreaches a Cmax after Cmax is reached for the clarithromycin releasedfrom the second dosage form.
 20. A process for treating a bacterialinfection in a host comprising: administering to a host the product ofclaim 1, once-a-day.
 21. A process for treating a bacterial infection ina host comprising: administering to a host the clarithromycin product ofclaim 2, once-a-day.
 22. A process for treating a bacterial infection ina host comprising: administering to a host the clarithromycin product ofclaim 3, once-a-day.
 23. A process for treating a bacterial infection ina host comprising: administering to a host the clarithromycin product ofclaim 4, once-a-day.
 24. A process for treating a bacterial infection ina host comprising: administering to a host the clarithromycin product ofclaim 5, once-a-day.
 25. A process for treating a bacterial infection ina host comprising: administering to a host the clarithromycin product ofclaim 6, once-a-day.
 26. A process for treating a bacterial infection ina host comprising: administering to a host the clarithromycin product ofclaim 7, once-a-day.
 27. A process for treating a bacterial infection ina host comprising: administering to a host the clarithromycin product ofclaim 8, once-a-day.
 28. A process for treating a bacterial infection ina host comprising: administering to a host the clarithromycin product ofclaim 9, once-a-day.
 29. A process for treating a bacterial infection ina host comprising: administering to a host the clarithromycin product ofclaim 10, once-a-day.
 30. A process for treating a bacterial infectionin a host comprising: administering to a host the clarithromycin productof claim 11, once-a-day.
 31. A process for treating a bacterialinfection in a host comprising: administering to a host theclarithromycin product of claim 12, once-a-day.
 32. A process fortreating a bacterial infection in a host comprising: administering to ahost the clarithromycin product of claim 13, once-a-day.
 33. A processfor treating a bacterial infection in a host comprising: administeringto a host the clarithromycin product of claim 14, once-a-day.
 34. Aprocess for treating a bacterial infection in a host comprising:administering to a host the clarithromycin product of claim 15,once-a-day.
 35. A process for treating a bacterial infection in a hostcomprising: administering to a host the clarithromycin product of claim16, once-a-day.
 36. A process for treating a bacterial infection in ahost comprising: administering to a host the clarithromycin product ofclaim 17, once-a-day.
 37. A process for treating a bacterial infectionin a host comprising: administering to a host the clarithromycin productof claim 18, once-a-day.
 38. A process for treating a bacterialinfection in a host comprising: administering to a host theclarithromycin product of claim 19, once-a-day.